Actin is one of the two major components of the cytoskeleton in eukaryotic cells, and it participates in many important cellular processes, including cell division, motility, and signaling. Natural product small molecules that inhibit acti cytoskeleton dynamics have long been recognized as valuable molecular probes for elucidating the cellular functions of actin. However, their potential use as chemotherapeutic agents in the treatment of cancer has just started to be recognized. Selective inhibition of the actin cytoskeleton could be a powerful strategy for chemotherapeutic intervention in cancer treatment. This proposal presents a highly convergent approach for the asymmetric total synthesis of rhizopodin employing multi-component Anion Relay Chemistry (ARC) pioneered by the Smith group, in conjunction with modern methods in catalysis and stereoselective synthesis. This synthetic approach will be adapted for the synthesis of novel structural analogs. All synthetic products will be subjected to biological evaluation. The ultimate goals of the proposed project are to discover potent and selective actin- targeting small molecules as chemotherapeutic agents in cancer treatment as well as to provide molecular probes to elucidate the role of the dimeric nature of rhizopodin in its mode of action. PUBLIC HEALTH RELEVANCE: Actin is one of the two major components of the cytoskeleton in eukaryotic cells and it participates in many important cellular processes, including muscle contraction, cell division, motility, and signaling. Discovery of small molecules that can selectively inhibit actin polymerization in cancer cells could lead to a powerful strategy for chemotherapeutic intervention in cancer treatment.